Risk factors for proliferative vitreoretinopathy after retinal detachment surgery: A systematic review and meta-analysis

Background To comprehensively investigate risk factors for proliferative vitreoretinopathy (PVR) after retinal detachment (RD) surgery. Methods PubMed, Embase, Cochrane Library, and Web of Science were systematically searched until May 22, 2023. Risk factors included demographic and disease-related risk factors. Odds ratios (ORs) and weighted mean differences (WMDs) were used as the effect sizes, and shown with 95% confidence intervals (CIs). Sensitivity analysis was conducted. The protocol was registered with PROSPERO (CRD42022378652). Results Twenty-two studies of 13,875 subjects were included in this systematic review and meta-analysis. Increased age was associated with a higher risk of postoperative PVR (pooled WMD = 3.98, 95%CI: 0.21, 7.75, P = 0.038). Smokers had a higher risk of postoperative PVR than non-smokers (pooled OR = 5.07, 95%CI: 2.21–11.61, P<0.001). Presence of preoperative PVR was associated with a greater risk of postoperative PVR (pooled OR = 22.28, 95%CI: 2.54, 195.31, P = 0.005). Presence of vitreous hemorrhage was associated with a greater risk of postoperative PVR (pooled OR = 4.12, 95%CI: 1.62, 10.50, P = 0.003). Individuals with aphakia or pseudophakia had an increased risk of postoperative PVR in contrast to those without (pooled OR = 1.41, 95%CI: 1.02, 1.95, P = 0.040). The risk of postoperative PVR was higher among patients with macula off versus those with macula on (pooled OR = 1.85, 95%CI: 1.24, 2.74, P = 0.002). Extent of RD in patients with postoperative PVR was larger than that in patients without (pooled WMD = 0.31, 95%CI: 0.02, 0.59, P = 0.036). Patients with postoperative PVR had longer duration of RD symptoms than those without (pooled WMD = 10.36, 95%CI: 2.29, 18.43, P = 0.012). Conclusion Age, smoking, preoperative PVR, vitreous hemorrhage, aphakia or pseudophakia, macula off, extent of RD, and duration of RD symptoms were risk factors for postoperative PVR in patients undergoing RD surgery, which may help better identify high-risk patients, and provide timely interventions.


Background
The success of retinal detachment (RD) surgery is dependent on the absence or control of proliferative vitreoretinopathy (PVR) [1].PVR, one of the most important complications following vitreoretinal surgery, is a fibrotic eye disease with an incidence of 5-11%, and characterized by migration and proliferation of cells following a break in the retina or trauma, leading to formation of membranes in the periretinal area, followed by contraction of the cellular membranes and traction on the retina that causes RD [2][3][4].For improvements in the surgical success rate and prevention of this complication, it is necessary to understand the risk factors for PVR in patients after RD surgery.
Several studies have been performed to explore the risk factors for PVR after RD surgery, but there are still inconsistent results.In the study of Xu et al. [5], macular involvement and cigarette smoking are factors predictive of PVR formation after uncomplicated primary RD repair.Bonnet et al. [6] illustrated that preoperative grade-B PVR and preoperative vitreous hemorrhage were associated with a significantly higher incidence of postoperative PVR.A history of uveitis related to an increased risk of PVR following RD surgery, according to another study [7].In cases of RD with pre-existing PVR, there is a significant risk of progression to further advanced PVR [8][9][10].Smoking was reported by Eliott et al. [11] to be a risk factor for PVR after the repair of RD associated with open-globe trauma.Another study showed that patients >70 years and with intraocular pressure lower than 14 mmHg had a higher risk of PVR after RD surgery [12].At present, only a systematic review protocol of Chaudhary et al. [10] is available, and no study comprehensively evaluates the risk factors for PVR after RD surgery.
This study intended to comprehensively probe into the risk factors for PVR after RD surgery via a systematic review and meta-analysis, and focused on demographic risk factors and disease-related risk factors.

Eligibility criteria
Inclusion criteria were: (1) studies on patients undergoing RD surgery; (2) studies reporting whether patients had PVR after RD surgery; (3) studies reporting at least one of the following: demographic risk factors and disease-related risk factors; (4) cohort studies and case-control studies; (5) studies in English; (6) the latest studies when the study population was repeated.
Exclusion criteria were: (1) studies with animal experiments; (2) studies unrelated to the research topic, such as studies on drug testing, etc.; (3) studies for which data are incomplete or data cannot be extracted; (4) conference reports, dissertations, case reports, meta-analyses, reviews.

Data extraction and quality assessment
Extracted data included first author, year of publication, country, study period, study design, sample size, preoperative PVR, sex ratio (male/female), age (years), follow-up time (months), disease type, type of surgery, quality assessment, and risk factor.The quality of the included case-control and cohort studies was evaluated using the modified Newcastle-Ottawa scale (NOS).The scale had a total score of 9, with 0-3 as low quality, 4-6 as medium quality, and 7-9 as high quality [13].

Statistical analysis
All studies were statistically analyzed using Stata 15.1 (Stata Corporation, College Station, TX, USA).For enumeration data, odds ratios (ORs) and hazard ratios (HRs) were used as the effect sizes, and for measurement data, weighted mean differences (WMDs) acted as the effect size, with 95% confidence intervals (CIs) calculated.The heterogeneity test was carried out for each index.If the heterogeneity statistic I 2 �50%, the random-effects model was used for analysis; otherwise, the fixed-effects model was used for analysis.Sensitivity analysis was carried out for all models.P<0.05 was considered to be statistically significant.

Characteristics of the included studies
A total of 6,477 studies were retrieved from the four databases, and 7 additional articles were identified from review studies.After deduplication, 3,495 were left.Subsequently, titles and abstracts and then full texts were subject to screening according to the eligibility criteria.Finally, 22 studies [5,7,11,12,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] of 13,875 subjects were included, published between 1984 and 2023.Fig 1 shows a flow chart of study selection.Three studies did not involve patients with preoperative PVR, some patients in 16 studies had preoperative PVR, and 3 studies did not report preoperative PVR.Of the included studies, 7 were cohort studies and 15 were casecontrol studies.All the studies were evaluated to have medium quality.Basic characteristics of the included studies are illustrated in Table 1.

Demographic risk factors
Sex. Eight studies of 1,875 patients reported the association between sex and the risk of postoperative PVR.No significant difference was observed in the risk of postoperative PVR between male and female patients (pooled OR = 1.17, 95%CI: 0.92, 1.49, P = 0.210, I 2 = 0.0%) (Fig 2A and Table 2).Moussa et al. showed that sex is not a risk factor for postoperative PVR (OR = 0.60, 95%CI: 0.26-1.39,P = 0.234).According to the study of Capeans et al., there is no gender difference between the postoperative PVR group and the postoperative non-PVR group, with a male proportion of 50% vs 42%, respectively.

Disease-related risk factors
Surgical history.Two studies on 575 patients estimated the risk of postoperative PVR in patients with a history of ophthalmic surgery.A history of ophthalmic surgery was not associated with a greater risk of postoperative PVR (pooled OR = 1.17 Vitreous hemorrhage.Vitreous hemorrhage was reported in 5 studies with 820 subjects.Presence of vitreous hemorrhage was associated with a significantly greater risk of postoperative PVR (pooled OR = 4.12, 95%CI: 1.62, 10.50, P = 0.003, I 2 = 52.9%)(Fig 3D and Table 2).
The study of Duquesne et al. showed that 11.3% of patients with preoperative vitreous hemorrhage and 11.8% of patients without preoperative vitreous hemorrhage developed PVR after Macula off.Macula off was assessed in 6 studies with 961 patients.The risk of postoperative PVR was significantly higher among patients with macula off versus those with macula on (pooled OR = 1.85, 95%CI: 1.24, 2.74, P = 0.002, I 2 = 47.2%)(Fig 3F and Table 2).
According to Cowley et al., patients with macula off accounted for 84.6% in the postoperative PVR group and 64.6% in the non-PVR group (P = 0.002), indicating that macula off is a risk factor for PVR after RD surgery.Loiudice et al. (OR = 2.13, 95%CI: 0.094, 48.33, P = 0.634), and Moussa et al. (OR = 0.52, 95%CI: 0.15, 1.82, P = 0.309) showed that macula status was not a risk factor for postoperative PVR.Capeans et al. found no difference in macula off between the postoperative PVR and non-PVR groups (30% vs 41%).
Extent of RD.Two studies with 246 patients provided information on extent of RD.Extent of RD in patients with postoperative PVR was significantly larger than that in patients   2).Loiudice et al. showed that extent of RD was not a risk factor for postoperative PVR (OR = 0.30, 95%CI: 0.04, 0. 2.26, P = 0.242).
Loiudice et al. demonstrated that the number of retinal breaks was not associated with PVR after RD surgery (OR = 0.64, 95%CI: 0.52, 2.86, P = 0.643).
Duration of RD symptoms.Three studies with 649 patients evaluated duration of RD symptoms.The overall results showed that patients with postoperative PVR had significantly longer duration of RD symptoms than those without postoperative PVR (pooled WMD = 10.36,95%CI: 2.29, 18.43, P = 0.012, I 2 = 40.7%)(Fig 3J and Table 2).

Sensitivity analysis
Sensitivity analysis was conducted by deleting a study at a time and synthetically assessing the remaining studies.It was found that the pooled results were not affected by one-study deletion, suggesting that the findings of this meta-analysis were stable and robust.

Discussion
This review and meta-analysis first comprehensively evaluated the risk factors for PVR after RD surgery from the perspectives of demographic and disease-related risk factors.It was revealed that age, smoking, preoperative PVR, vitreous hemorrhage, aphakia or pseudophakia, macula off, extent of RD, and duration of RD symptoms were risk factors for postoperative PVR in patients undergoing RD surgery.Combined assessment of demographic and diseaserelated risk factors may aid in better prediction of the PVR risk following RD surgery.Awareness of these factors in the development of PVR may allow for early lifestyle interventions and careful surgical planning to minimize the risk.
As regards demographic risk factors, older age was associated with a higher risk of PVR after RD surgery.Apart from the included studies that supported the above statement [12,20,26], no other studies are found to support the statement.Future evidence is needed to confirm this finding.A possible explanation for this finding is that increased signaling of proinflammatory cytokines in patients with older age can promote the progression of PVR [31,32].The lack of research on the underlying mechanism necessitates future studies.We also found that smoking was predictive of postoperative PVR formation.Cigarette smoking may influence the integrity of the blood-retinal barrier since the breakdown of the blood-retinal barrier was considered to be related to the formation of PVR [33].Afterwards, serum components (such as fibronectin and platelet-derived growth factor) invaded the vitreous and accelerated the migration and proliferation of retinal pigment epithelial cells released into the vitreous after RD.Additionally, smoking was correlated with the development of uveitis and retinal neovascularization [34,35].Wang et al. [36] indicated that the increase of pro-inflammatory cytokine signaling could play an essential role in the development of PVR in smokers.More investigations are needed to clarify the role of smoking in the risk of PVR after RD surgery.Although smoking was reported to be a risk factor for eye diseases [37], a small number of smokers (about 10-13%) realized that smoking can cause visual impairment [38].In optometric practice, nearly 45% of optometrists did not evaluate patients' smoking status at the initial visit and 8% of the optometrists never updated patients' smoking status [39].Besides, 2.3% of optometrists never explained the adverse effect of smoking on eye health to patients [39].Thus, it is very important for vitreoretinal subspecialists, comprehensive ophthalmologists, and optometrists who provide primary eye care to highlight the negative impact of smoking.Eye care professionals should provide smoking cessation programs for patients undergoing RD surgery.Quitting smoking after diagnosis of RD should be advocated as a potential timely intervention for this public health concern.
With respect to disease-related risk factors, patients with preoperative PVR, vitreous hemorrhage, aphakia or pseudophakia, macula off, large extent of RD, and long duration of RD symptoms had an elevated risk of postoperative PVR.Scare evidence has been provided on the role of preoperative PVR in such a setting.Bonnet et al. [6] illustrated that preoperative PVR and vitreous hemorrhage were correlated with a significantly higher incidence of postoperative PVR.According to a prior review, individuals with vitreous hemorrhage had high odds of many diseases, including PVR [40].We assume that the association between vitreous hemorrhage and postoperative PVR is attributed to high levels of cytokines.Preoperative aqueous flare values may increase as extent of RD becomes large [41], and the flare values may predict PVR re-detachment [17], which may contribute to the association between extent of RD and the risk of postoperative PVR.As regards the relationship between duration of RD symptoms and postoperative PVR, we speculated that long duration of RD symptoms provides time for retinal pigment epithelium cells to migrate, proliferate and generate extracellular matrix, resulting in contracted membrane on the anterior or lower surface of the retina, fixed retinal folds and retinal traction [42].Concerning the associations of aphakia or pseudophakia and macula off with the risk of PVR following RD surgery, more investigations are warranted to confirm and elaborate on these associations.This work may act as a reference for vitreoretinal surgeons, and the identified evidence may help the standardization of clinical practice, with more effective management bringing improved outcomes for patients following RD surgery.Given the risk factors, patients should pay attention to and practice smoking cessation and eye care to prevent and lower the risk of postoperative PVR.Targeted screening strategies and interventions could be developed for individuals at a high risk of PVR after RD surgery.Some limitations of this study should be noted.First, the results of combined analysis may be unstable due to the existence of heterogeneity.Second, confounding factors were not taken into account when evaluating these risk factors.Third, the study only included English literature, which may cause language bias.Besides, of 22 included studies, 9 studies [5,9,11,12,15,17,19,20,22] reported a mixture of vitrectomy and scleral buckling (SB) (and, in 2 studies [15,20], other types of surgery), 1 study [16] reported SB and pneumatic retinopexy, and 1 study [7] did not report the type of surgery.Subgroup analysis could not be performed based on the type of surgery (vitrectomy, SB).The aggressiveness and progression of PVR in post vitrectomy and post SB can be different.Pars plana vitrectomy (PPV) plus SB was associated with a higher risk of PVR re-detachment than PPV alone [11].Additionally, the surgical method may vary among patients with different demographic characteristics.For example, 73% older patients with rhegmatogenous retinal detachment underwent PPV [43].Thus, pooled evaluation of PVR in all PPV/SB cases may increase the heterogeneity of this study, which further affect the stability of the results.For another, the results of this pooled evaluation may be applicable to patients undergoing either vitrectomy or SB.Future research is needed for verification regarding heterogeneity and applicability.Furthermore, since most studies reported admixed surgical population (some PPV, some SB in each study) and original data among these studies could not be obtained, separate analysis regarding only cases undergoing micro-incision vitrectomy surgery (MIVS) seems not feasible, which requires more explorations.

Conclusion
Age, smoking, preoperative PVR, vitreous hemorrhage, aphakia or pseudophakia, macula off, extent of RD, and duration of RD symptoms were risk factors for PVR following RD surgery.Future studies are warranted to support our findings.
. Ferrara et al. found that elderly patients showed more severe PVR (grade C and above), especially after 60 years old.Kasetty et al. illustrated a higher incidence of PVR in young patients.Gao et al., Loiudice et al. and Moussa et al. reported that age is not a risk factor for postoperative PVR.

Table 1 . Basic characteristics of the included studies.
preoperative PVR grade B: OR = 1.491,P = 0.047), and Cowley et al. (53.8% vs 11.1%, P<0.01) demonstrated that preoperative PVR was a risk factor for redetaching due to postoperative PVR.History of uveitis.The data on a history of uveitis were provided by 3 studies with 1,098 patients.The overall result showed no significant difference in the risk of postoperative PVR